Racemic amines may be enantiomerically resolved using various physico-chemical separation techniques after derivation with a tag molecule. M. Pawlowska et al. disclose a method for enantiomerically separating aliphatic and aromatic amines using aromatic anhydrides as nonchiral derivatizing agents. (Journal of Chromatography A. (1994): vol. 666(1-2):485-91.) Alternatively, T. Toyo'oka et al. disclose a method for enantiomerically separating amines using chiral tagging reagents and high-performance liquid chromatography. (Biomedical Chromatography (1994): vol. 8(2):85-9.)
Racemic amines may also be enantiomerically resolved without tagging or derivation using various chiral physico-chemical separation techniques. N. Huynh et al. disclose a chromatographic separation of enantiomeric amines using N-benzyloxycarbonyl-glyclyl-L-proline as a counter ion in methanol. (Journal of Chromatography A. (1995): vol. 705(2):275-87. S. Branch et al. disclose a separation method employing capillary electrophoresis with cyclodextrins for separating enantiomers of phenethylamine. (Journal of Pharmaceutical & Biomedical Analysis (1994): vol. 12(12):1507-17. R. Kuhn et al. disclose the use of capillary zone electrophoresis with optically active crown ethers for separating enantiomers. (Electrophoresis (1994): vol. 15(6):828-34.) J. Mazzeo et al. disclose the use of micellar electrokinetic capillary chromatography using novel chiral surfactants for separating enantiomers of amines. (Journal of Chromatography A. (1994): vol. 680(1):125-35.)
Amines may also be enantiomerically resolved by the enzymatic formation of amides using esters as substrates. (H. Kitaguchi, et al., J. Am. Chem. Soc., (1989): vol. 111, pp 3094; S. Fernandez et al., J. Chem. Soc. Chem. Commun. (1992): pp 2885; and V. Gotor, et al., J. Chem. Soc. Chem. Commun. (1993): pp 2453.) These unsymmetrical carbonates are, however, not readily available and may be too reactive to avoid non-enzymatic reactions. Methods for protecting amines by derivation with vinyl carbonates using the lipase from Candida antarctica have been reported. (M. Pozo, et al., Tetrahedron (1992): vol. 48, pp 6477; M. Pozo et al., Tetrahedron (1993): vol. 49, pp 10725.)
Unlike the enantiomeric resolution of amines, methods for the enantiomeric resolution of alcohols are relatively well developed. Racemic alcohols may be resolved by an irreversible enzymatic acylation using lipases or serine proteases as catalysts in high concentrations of organic solvents. Preferred acylation reagents include activated esters such as trifluoroethyl-, choloroethyl-, cyanomethyl-, enol-, oxime- or thioesters, or anhydrides. Methods for enzymatically acylating alcohols have been extensively reviewed. (Klibanov. A., Acc. Chem. Res. (1990): vol. 23, pp 114; Wong, C.-H. et al., Enzymes in Synthetic Organic Chemistry, Pergamon, Oxford, 1994, pp 72; and J.-M. Fang, J.-M et al., Synlett. (1994): vol. 6, pp. 393.) Enol esters are preferred acylating reagents for alcohols. (See: H. M. Sweers et al., J. Am. Chem. Soc. (1986): vol. 108, pp 6421; M. Degueil-Castaing, et al., Tetrahedron Lett. (1987): vol. 28, pp 953; Y. Wang, et al., J. Am. Chem. Soc. (1988): vol. 110, pp 7200; and K. Laumen, et al., J. Chem. Soc., Chem. Commun. (1988), pp 1459.) The rate of enzymatic acylation for enol esters is relatively fast. Furthermore, since the released enol is spontaneously tautomerized to a ketone, the process irreversible and free of any inhibition that might be caused by the leaving alcohol. The product is easy to isolate. These acylating reagents, however, can not be used in the enzymatic acylation of amines as they are too reactive and give high background reactions.
What is needed is a method for enantiomerically resolving amines by an enzymatic derivation with homocarbonates to form chiral carbamates.